Process for preparing substituted 9,10-dioxo-9,10-dihydroanthrecenes and 6H-anthra[1,9-cd]isoxazol-6-ones

Abstract

The disclosure provides processes of preparing compounds of Formula (I) and Formula (IV), their salts, and intermediates thereof, wherein R 1 , R 2 , R 3 , and R 7 are defined as set forth in the specification.

What is claimed is: 
     
       1. A process for preparing a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, 
       wherein:
 R 1  is optionally substituted aryl; 
 R 2  is NRor CR 9 R 10 ; 
 R 3 , R 9 , and R 10  are independently selected from the group consisting of hydrogen, halogen, CN, NH 2 , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, —(CHR) n C 6-10  aryl, —(CHR) n C 5-8  heterocycle, —(CHR) n C 3-8  cycloalkyl, —O—C 6-10  aryl, —O—C 5-10 heterocycle, —C(O)CF 3 , —(CH 2 ) n halogen, —(CHR) n —O) n —C(═O)R 8 , —(CHR) n —(S) n —C(═O)R 8 , —OR a , —NR 11 R 12 , —NR a COR 11 , —NR a COOR a , —NR a SO 2 R, —NR a CONR 11 R 12 , —COR a , —(CHR) n COOR a , —S—C 1-6  alkyl, and —CONR 11 R 12 , wherein each said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle is independently optionally substituted with 1 to 2 groups independently selected from C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 13 , or NR a SO 2 R 13 ; 
 R 7  is hydrogen, halogen, CN, C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, —(CHR) n C 6-10  aryl, —(CHR) n C 5-8  heterocycle, —(CHR) n C 3-8  cycloalkyl, —C(O)CF 3 , —(CH 2 ) n halogen, —COR a , —(CHR)nCOOR a , and —CONR 11 R 12 , wherein each said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle is independently optionally substituted with 1 to 2 groups independently selected from C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 13 , or NR a SO 2 R 13 ; 
 R 11  and R 12  are independently selected from the group consisting of hydrogen, N(R a )C(═O)R, halogen, CN, NH 2 , NHR a , NO 2 , C 1-4  haloalkyl, —OC 1-4  haloalkyl, C 1-6  alkyl, C 2-8  alkenyl, —S—C 1-6 alkyl, —C(═O)—(O) n —R a , —(CHR) n —(O) n —C(═O)R 8 , —(CHR) n —(S) n —C(═O)R 8 , —OR a , —(CHR) n C 3-10  cycloalkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 5-10  heteroaryl, and —(CHR) n C 5-10  heterocycle, wherein each said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocycle is independently optionally substituted with 1 to 2 groups independently selected from C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 13 , or NR a SO 2 R 13 , and wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; alternatively, R 11  and R 12 , taken together with the atom(s) to which they are attached, form a 3 to 6 membered heterocyclic group containing one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the heterocyclic group is optionally substituted with 1 to 2 groups independently selected from C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 13 , or NR a SO 2 R 13 ; 
 R each independently represents hydrogen, halogen, CN, NO 2 , NH 2 , or C 1-6  alkyl; 
 R a  each independently represents hydrogen or C 1-6  alkyl; 
 R 8  each independently represents C 1-6  alkyl, halogen, CN, NO 2 , NH 2 , NHR a , SO 2 R 13 , or NR a SO 2 R 13 ; 
 R 13  is hydrogen, C 1-6  alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle; and 
 n represents an integer from 0 to 3; 
 said process comprising reacting a compound of Formula II: 
 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is optionally substituted aryl; 
         with 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 2  and R 3  are defined as above; 
         to give said compound of Formula I. 
       
     
     
       2. The process of  claim 1 , wherein said reacting step is carried out in a polar, aprotic solvent. 
     
     
       3. The process of  claim 1 , wherein said reacting step takes place in the presence of a base. 
     
     
       4. The process of  claim 3 , wherein the base is triethyl amine. 
     
     
       5. The process of  claim 1 , further comprising:
 subjecting the compound of Formula I or a salt thereof: 
 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , and R 3  are defined as in  claim 1 , 
         to conditions that result in an intramolecular ring closing reaction to form a compound of Formula IV: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein: 
         R 1 , R 2 , and R 3  are defined as in  claim 1 . 
       
     
     
       6. The process of  claim 5 , wherein said process further comprises:
 reacting the compound of Formula I or a salt thereof: 
 
       
         
           
           
               
               
           
         
         with a nitrite in the presence of an acid to form a compound of Formula V: 
       
       
         
           
           
               
               
           
         
       
     
     
       7. The process of  claim 6 , wherein in the nitrite is sodium nitrite and the acid is sulfuric acid. 
     
     
       8. The process of  claim 6 , wherein the reaction is carried out at a temperature from about 35° C. to about 75° C. 
     
     
       9. The process of  claim 6 , wherein said process further comprises:
 reacting the compound of Formula V with an azide in the presence of a solvent to form a compound of Formula VI: 
 
       
         
           
           
               
               
           
         
       
     
     
       10. The process of  claim 9 , wherein in the azide is sodium azide and the solvent is water. 
     
     
       11. The process of  claim 9 , wherein the reaction takes place in a period of time of about 6 hours to about 18 hours. 
     
     
       12. The process of  claim 9 , wherein said process further comprises:
 heating the compound of Formula VI in the presence of a solvent to form a compound of Formula IV. 
 
     
     
       13. The process of  claim 12 , wherein the solvent is toluene. 
     
     
       14. The process of  claim 12 , wherein the reaction is carried out at a temperature from about 50° C. to about 90° C. 
     
     
       15. The process of  claim 5 , wherein said process further comprises:
 1) reacting the compound of Formula I or a salt thereof: 
 
       
         
           
           
               
               
           
         
         with a nitrite in the presence of an acid to form a compound of Formula V: 
       
       
         
           
           
               
               
           
         
         2) reacting the compound of Formula V with an azide in the presence of a solvent to form a compound of Formula VI: 
       
       
         
           
           
               
               
           
         
          and 
         3) heating the compound of Formula VI in the presence of a solvent to form a compound of Formula IV. 
       
     
     
       16. The process of  claim 1 , further comprising reacting a compound of Formula III: 
       
         
           
           
               
               
           
         
         with H 2 NR 1    
         wherein: 
         R 1  is optionally substituted aryl; 
         to give said compound of Formula II: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is optionally substituted aryl. 
       
     
     
       17. The process of  claim 16 , wherein said reacting step is carried out in cyclohexyl alcohol. 
     
     
       18. The process of any one of claims  claim 16 , wherein said reacting step takes place in the presence of copper (II) acetate, copper metal, and potassium acetate. 
     
     
       19. The process of  claim 1 , wherein:
 R 1  is 
 
       
         
           
           
               
               
           
         
         R 4  is COOH; 
         R 4a  is hydrogen; 
         R 2  is NR 7 ; 
         R 3  is H; and 
         R 7  is cyclohexyl.